Antiepileptic drugs

Dr. Hj. Rika Yuliwulandari, PhD

Definisi
Tujuan antiepileptic drugs
Classification of antiepileptic drugs
Pharmacology of antiepileptic drugs

Definition
Epilepsy:
Recurrent seizure disorders
Sudden
Excessive
Symptoms depend on the site of electrical discharge
Convulsion motor cortex
Visual, auditory, olfactory hallucinations parietal or occipital cortex

Antiepileptic drugs:
Treat 50% of patient with convulsion
Tappering on ----- tappering off
Goal:
Stop convulsion
Not harmful for cerebral neurons
Normal activity post treatment

Antiepileptic Drugs Classification

Golongan hidantoin
Fenitoin (difenilhidantoin), mefenitoin, etotoin
Golongan barbiturat
Fenobarbital, primidon
Golongan suksinimid
Etosuksimid, metsuksimid, fensuksimid
Karbamazepin
Golongan benzodiazepin
Diazepam, klonazepam, nitrazepam
Asam valproat
Antiepilepsi lain
Lamotrigin, gabapentin, Asetazolamid, vigabatrin,

Principle Mechanisms of Action of Anti

epileptic Drugs
Decrease activity of voltage-dependent
Na+ channels
Decrease activity of voltage-dependent
Ca+ channels
Augment GABA activity
Decrease glutamate receptor activity

Clinical Application of
Antiepileptic Drugs
Types of
epilepsy

Drugs 1

Drugs 2

-Simple

Phenitoin, CBZ

Phenobarbital, Primidone

- Complex

Phenitoin, CBZ

Primidone

- Tonic-Clonic
(grand mal)

Phenytoin, CBZ

Phenobarbital, Primidone,
Valproic acid

- Absence
(Petit mal)

Ethosuximide

Valproic acid, Clonazepam

- Myoclonic

Valproic acid,
Clonazepam

-Febrile
Seizures in
children

Phenobarbital

Primidone

- Status

Phenitoin,

Phenobarbital

PARTIAL

GENERALIZED

Phenytoin
Hydantoin group
Phenytoin (Dephenylhydantoin)
Mefenytoin
Etotoin

Pharmacology:
Na flux in neurons
Effect: Drowsiness, lethargy without hypnosis
Absorption: slow (i.m. is deposited in injection site for 5 day
s)
Distribution is rapid
High concentration in brain
Mostly bound to plasma albumin
T1/2: 7-42 hrs
Protein binding: 90%

 Metabolism: hepatic hydroxylation system

Drug induced toxicity is easy to occur (need tight monitoring!!!)
Genetic variation affect the drug metabolisms
Dose: 200-400 mg (5-10 mg/kgbw)
Se:

GI problems: nausea, vomiting

Gingival hyperplasia and coarsening of facial features esp. in children
Megaloblastic anemia
Behavioral changes: confusion, hallucination, drowsiness
Inhibit insulin secretion causing hyperglycemia and glycosuria
Pregnancy: teratogenic effect ---- fetal hydantoin syndrome (cleft lip, clef
t palate, congenital heart disease, slow growth and mental deficiency)

Drug interaction:
Inhibition of Phenytoin: Chloramphenicol, Dicumarol, Cimetidine, Sulfon
amide, Isoniazid
Increase Phenytoin metabolism: Carbamazepine, Teophylline, Phenobar
bital
Phenytoin induce P-450 system---- increase metabolism of other antiepil
eptics, anticoagulants, oral contraceptives, quinidine, Doxycycline, Cyclo
sporin, Mexiletine, Methadone, Levodopa

Carbamazepine
Moa: blocking Na channel
Pharmacology:
Absorption: slow
High lipid solubility --- rapidly enter the brain
Enhance hepatic P-450 system ---- in chronic administration, t1/2 decrease
Dose: 400-1200 mg (Child: 10-30 mg/kgbw)
T1/2: 8-24 hrs
Protein binding: 75%
Po only
Se:
Chronic use: stupor , coma, respiratory depression, drowsiness, vertigo, ataxia, blurred visi
on
GI problem: nausea, vomiting
Aplastic anemia, agranulocytosis, thrombocytopenia
Potentially induce liver toxicity (need frequent liver function test!!!!)

Drug interaction:

Allert: Carbamazepine and most other antiepileptic drugs required grad

ual dose titration to full dose over days to weeks, except Phenytoin

Phenobarbital
Family of barbiturate:
Phenobarbital
Primidone

Pharmacology:
Moa: Potentiate inhibiton effect of GABA (gamma aminobutyr
ic acid)-mediated neurons
Absorption:
Oral: well absorbed
Potent inducer of P450
Almost 75% is inactivated in liver, the rest is excreted through kidney

Se:

Sedation, ataxia, nystagmus, vertigo, acute psychotic reactions

Sensitive individual: nausea, vomiting, morbiliform rash
High dose: agitation, confusion
Discontinuation: rebound seizures

Primidone
Resembles Phenobarbital
Orally well absorbed
Poor protein binding

Valproic acid
Moa: enhance GABA action at inhibitory synapses
Uses: most effective for myoclonic seizures
Pharmacology:
Orally well and rapid absorbed
Protein binding: 90%
3% excreted unchanged, the rest become active metabolite
Metabolized in liver by P450 system
Dose: 750-3000 mg (child: 15-60 mg/kgbw)
T1/2: 6-16 hrs
Se:
nausea, vomiting, sedation, ataxia, tremor
Rash and alopecia in some individuals
Increase bleeding time due to thrombocytopenia and inhibition of platelet aggre
gation

Drug interaction:
Inhibits phenobarbital metabolism causing increase circulating level of the drug

Ethosuximide
Family of Suximide
Ethosuximide, Metsuximide,Fensuximide

Pharmacology:
Moa: inhibit Ca channel in neuron T cell of thalamus
Well absorbed orally
Protein binding: 0%
25% excreted unchanged in urine
75% is inactivated in liver
Does not induce P450 system
Dose: 500-1500 mg (child: 15-30 mg/kgbw)
T : 20-60 hrs
Se:
stomach irritation, nausea, vomiting, drowsiness, lethargy, dixxiness, restles
sness, agitation, anxiety, inability to concentrate
Sensitive individual: Stevens-Johnsons syndrome, urticatia, leukopenia, apla
stic anemia, thrombocytopenia

Diazepam
Family of Benzodiazepine
Diazepam, Klonazepam, Nitrazepam

Pharmacology:
Doc of acute treatment in status epilepticus
Dose:
5-20mg iv (slow) ---- can be repeated after 15-2
0 mnt
Infant: 0.5mg/kgbw per rectal, child <11 yr: 1 m
g/kgbw

Se: respiratory tract obstruction, respiratory

depression, hypotension, cardiac arrest, sle

Other antiepileptic drugs

Gabapentin:
Analog of GABA
Protein binding: 0%
Excreted unchanged in urine ---- minimize drug interaction
Dose: 900-3600 mg
T1/2: 5-7 hrs
Se: mild CNS

Lamotrigine:
Moa: inhibit glutamate and aspartate release, blocks sodium channels, prevent
s repetitive firing
Protein binding: 55%
Metabolized in liver
Dose: 100-600 mg
T1/2: 15-70 hrs
Se: mild CNS effect,rash
Drug interaction:
T1/2 is inhibited by P450 enzyme inducing drug (CBZ, Phenytoin)
T is Increased by valproic acid

Read
Patophysiology of convulsion